The most important risk factor for the development of osteoarthritis (OA) is age but the mechanisms by which aging contributes to OA susceptibility are poorly understood. A key feature of OA is the progressive destruction and loss of articular cartilage resulting from an imbalance in chondrocyte anabolic and catabolic activity. The long-term objective of this project is to determine the mechanisms by which aging contributes to this imbalance. Maintenance of the integrity of articular cartilage requires a properly orchestrated response of the chondrocyte to cell signals generated by growth factors, cytokines, and the extracellular matrix. This project focuses on the specific cellular and molecular mechanisms responsible for an age-related decline in the chondrocyte response to a key cartilage growth factor, IGF-I. Recent studies provide novel evidence that age-related oxidative stress may play a key role in reducing the chondrocyte response to IGF-I and, furthermore, could alter the activity of cell signaling pathways resulting in an imbalance in anabolic and catabolic activity as well as reduced cell survival. It has also been found that chondrocytes express RAGE (receptor for advanced glycation end-products). RAGE signaling is known to increase ROS production and activate NF B, initiating a pro-inflammatory state. An age-related increase in oxidative stress has been found to be a key contributor to aging processes in a number of tissues but its role in cartilage aging has received little attention. Therefore, the overall hypothesis to be tested in the continuation of this project is that an age-related chondrocyte resistance to IGF-I stimulation is due to dysregulated cell signaling resulting from the chronic and accumulated effects of oxidative stress and a resultant "pro-inflammatory" state. The specific aims will be to: 1) Measure the response of human articular chondrocytes, isolated from donors of different ages, to IGF-I when the cellular redox status has been modulated; 2) Determine the redox sensitive cell signaling mechanisms which regulate the chondrocyte response to IGF-I; and 3) Determine the contribution of the receptor for advanced glycation end-products (RAGE) to chondrocyte redox signaling and inhibition of the IGF-I response. The results from this project should continue to provide new information needed to establish the basic cellular and molecular mechanisms which link aging to the development of OA in humans.